The sudden infant death syndrome (SIDS) is the leading cause of postneonatal death in the United States, with an incidence of 1.5/1000 live births. We propose to focus upon the most promising lead that has emerged from our studies in SIDS brains: a deficiency of muscarinic cholinergic receptor binding in the arcuate nucleus of the ventral surface of the medulla. Our overall hypothesis that SIDS, or a subset of SIDS, is due to abnormality of the arcuate nucleus, a component of the ventral surface cell populations of the medulla which are putatively involved in chemosensitivity to carbon dioxide and hydrogen ion, cardiopulmonary coupling, and pressor responses. This abnormality results in a failure of the affected infant to respond to a life-threatening challenge, such as hypercarbia or asphyxia, during sleep, and leads to sleep-related sudden death during a vulnerable period in the development of homeostatic control. Our SPECIFIC AIMS over the next 4 years are: l. To test the hypothesis that the neurotransmitter abnormality in the arcuate nucleus in SIDS victims is confined to the muscarinic cholinergic receptor. This study will be done by determining if there is an abnormality in serotoninergic, kainate, or GABAergic binding, three other markers of the arcuate nucleus, in SIDS victims compared to age-matched controls using quantitative receptor autoradiography. 2. To test the hypothesis that there is altered serotoninergic binding in the caudal raphe of SIDS victims compared to aged-matched controls. We have preliminary evidence that the human arcuate nucleus is interconnected with the caudal raphe. Animal studies indicate the caudal raphe and its major neurotransmitter serotonin is involved in cardioventilatory function, and that the caudal raphe projects to medullary and cord nuclei critical to cardioventilatory regulation. This study will be done using 3H-LSD binding to serotoninergic receptors. 3. To characterize further the cholinergic anatomy of the developing human arcuate nucleus. 4. To characterize further receptor binding patterns to selected neurotransmitters and neuromodulators which are postulated to be involved in ventral surface function in animals. 5. To determine the connections of the human arcuate nucleus and its pre- and postnatal development using the fluorescent tracer DiI to label projections in postmortem brainstem tissues. At the end of the 4-year period, this grant should lead to a greater understanding of the role of the human arcuate nucleus in SIDS. It should also provide a solid anatomic foundation for hypothesis-driven experiments in an animal model for SIDS based upon a muscarinic cholinergic defect in the immature ventral medullary surface.